Malaria is the most common infectious human disease caused by parasitic protozoans. The disease is caused by infection with malaria parasites and is mediated by the mosquito, Anopheles gambiae. Every year there are estimated 500 million cases of malaria infection, including more than two million fatal cases (Gardner, et al., Nature 419:498-511, 2003). At present 40% of the world's population lives in malaria-epidemic areas, where it is said that one in every three infants dies from malaria.
Glycosylphosphatidylinositol (GPI) is known to play a key role in the growth and infectivity of parasites, including malaria parasites. There are many GPI-anchored proteins on the cell surface of these parasites. GPI-anchored proteins include proteins such as MSP-1 that function when the parasites invade red blood cells. GPI-anchored proteins act as parasitic antigens and initiate an immune response in the host. Thus, they have long been the subject of research aimed at vaccine development.
GPI not only functions as an anchor to tether proteins to the cell membrane, but is also an abundant glycolipid component of malaria parasite cell membranes. Recent studies have revealed that GPI is toxic and causes lethal symptoms. GPI induces the expression of inflammatory cytokines such as TNF-α, and of adhesion molecules. As a result, infected red blood cells adhere to capillaries, obstructing vessels (sequestration), brain blood vessels in particular. This induces further inflammatory reactions that are believed to lead to encephalopathy. Very recently, Schofield et al. reported that an anti-GPI antibody reduces lethality in an in vivo infection model system using the murine malaria parasite Plasmodium berghei, and that in vitro, the antibody inhibits late inflammatory reactions caused by Plasmodium falciparum (Schofield L, et al., Nature 418:785-789, 2002). These findings suggest that GPI is a major factor in the lethality of malarial infections.
It has also been reported that the acylation of inositol is essential for binding mannose to GPI (Gerold, P. et al., Biochem. J. 344:731-738, 1999), and that the inhibition of inositol acylation, caused by excess glucosamine, inhibits the maturation of the malaria parasite P. falciparum (Naik, R. S. et al., J. Biol. Chem. 278:2036-2042, 2003). Thus, compounds that can selectively inhibit GPI biosynthesis, particularly the acylation of inositol, may be highly useful antimalarial drugs.